DE2352615A1 - NEW ESTERS AND AMIDES OF 3-ARYL-1,4BENZODIOXANE-2-CARBONIC ACID - Google Patents

Description

PATENT LAWYERS

H. LEINWEBER mim. ing. H. ZIMMERMANN DIPL..ING. A. Gf. v. WENGEESKY ■ ^ '^ ,,

235261S

8 Munich 2, rosenta! 7, 2nd ed.

Tsi.-Adr. Lelnpat Munich Telephone (Q89) 26Q3989

Pogtscheielc account: Munich 22Q 45-804

. 4m October 19, 1973

IIII / Q

BI / S343 / 3m

LÜSO FAEMACQ B ¹ ITALIA Β, τΛ. ^ MUmA _r Italy leue Ester imd Amid © der

-.-. J .'—. ... 1U..J. J. '· 1. 1 --U. ^a V> ..J. ^ ¹ JIi Il "». '! ■ !! in «ιιι (ι« · .-,

The charge applies to the following formula

(i)

in which Ar the meaning of a monooarhocyelis see, or, unsubstituted aryl group such as vinyl or s Phenyl owns one or more of the same or different May have substituents, such as Nledrigalkyl., Z, B »methyl, ethyl, n-propyl and isopropyl, or limbalkoxy, such as methoxy ^ ethoxy, n-propyloxy, isopropyloxy and n-butyloxy, or halogen, such as fluorine, Chlorine or bromine, and X the meaning of either Ca) a QR-Grru £ - ' pe, in which R is the meaning of hydroxyalkyl, z-.B. 2-hydroxyethyl, 3-hydroxypropy 1 and 2,3-dihydroxypropy 1, or W -, aminoalkyl, ζ. B.

2-diethylaminoethyl, 2-morpholinoethoxyethyl and 2-piperidino ethyl, or Ui-aminoalkoxyalkyl, e.g. 2-diethylaminoethoxyethyl, 2-morpholinoethoxyethyl or 2-piperidinoethoxyethyl, own, or from (b) one

-if _v group, in which R ₁ and R _{9 are the} same or ^ R ' ^ά

can be different and hydrogen, hydroxy, lower alkyl or carbocyclic monocyclic aryl, in particular Phenyl or monocarbocyclic arylalkyl groups, in particular Phenylalkyl, or the substituents R ^, or Rp together a Ι, Ν-Alkyleniinogruppe, a Κ, Ι-Oxoalkyleniiiiinogruppe, a Ι, Ι-thioalkylenimino group or a ff »I-azoalkylenimino group mean in which the alkylene has 3 to 8 carbon atoms and the aza nitrogen is substituted can be. The Gkcuppe

-If can thus be an I-monosubstituted amino group,

such as N-alkylamines, e.g. Met hjl amino, lthylamino or I-propylamino, N-cycloaklylamino, ζ · Β. I-cyclohexylamino _T I-arylalkylamino, such as benzylamino, or I-dialkylaminoäthylafflino, e.g. NjN-diethyläthylendiaiiiirto, or I-arylanino, such as li-phenylamino or substituted I-phenylamino, or an I, I-disubstituted amino group, such as 1, dialkylamino, eg IT, ^1-dimethyl: thylaniino, N-methyl 1-I-ethylamino _t I, I-Diäthyiamino, I, I-di-n-propylamino, and "N-diisopropylamino, or a cyclic group such as 1! -Pyrrolidinyl, 1-piperidinyl, 2-methyl-1-piperidinyl, ^ hydroxy- ^ phenyl-t-piperidinyl, 4-hydroxy-4-p-chlorophenyl-1-piperidinyl, ^ carboxyamino- ^ phenyl- 1-piperidinyl ,, 4-Benzoylaittine Q-i-'piperidinyl, 4-p-fluorobenzoyl-i-piperidinyl, 1-1,1- (1,6-hexylene) intino, 1-1,1- (1,7-heptylene) imino, 4 -14Or- ^: pholinyl and 4-thiomorphoninyl, or an!, I-azaalkylenimino-! mean group in which the alkylene has 4 to 6 carbon

409817/1195 - _: > -

has atoms and the "aza" nitrogen. through lower alkyl, j ■ eg methyl, ethyl and propyL, lower hydroxyalkyl, eg j hydroxyethyl. or lower arylalkyl, for example benzyl and 2- | Phenylethyl, or by monocarbocyclic aryl, preferably phenyl, which is optionally substituted by halogen, allyl or lower alkoxy, e.g. phenyl, 2-tolyl, 2,3-xy- ι IyI, 4-chlorophenyl or 2- ^ methoxyphenyl, such as in particular '1-piperazinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4- (2-hydroxyethyl) -1-piperazinyl, 4-phenyl-1-piperazinyl, 4-phenyl-Vpiperazinyl, 4-p-chlorophenyl-1-piperazinyl or
4-2 * -methoxyphenyl-1-piperazinyl can be substituted.

The invention also relates to the salts of the compounds of formula I with pharmaceutically acceptable inorganic salts, such as salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, i organic carboxylic acids such as acetic acid, propionic acid, glycol -; colic acid, malonic acid, succinic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, glucuronic acid, benzoic acid, mandelic acid, salicylic acid,
4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, palmitic acid (pamoic-acid), nicotinic acid and isonicotinic acid, as well as organic sulfonic acids, such as methanesulfonic acid,: ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disul- _; fonsäure, p-toluenesulfonic acid and naphthalene-2 ^ sulfonic acid. ί Mono- or poly-salts are formed according to the salt-forming groups present in the molecules. ;

The invention also provides a method of manufacturing of the compounds of the formula I. According to one process, the compounds are formed by reacting a carboxylic acid of the formula

COOH

(II)

4 0 9 8 1 7 / r 1 9 &

in which Ar is as defined above, or a suitable derivative, e.g. an ester (e.g. a methyl, ethyl or benzyl ester), a halide (such as chloride or bromide) or a mixed anhydride, with a low molecular weight aliphatic acid (such as acetic or propionic acid) with an alcohol of the formula III

R-OH (III)

in which R has the above meaning, or with an amine of the formula

MH (IV)

in which R * and Rp have the above meaning.

The reaction between an ester of the formula II. (E.g. an ethyl ester) and an alcohol of the formula III can be carried out by suspending the reagents in a hydrocarbon solvent (e.g. pentane or heptane) and in the presence of a basic catalyst such as sodium ethylate, heated, wherein the ethanol formed in the reaction or another alcohol is removed as an azeotropic mixture with the solvent. If, however, the ester of formula is reacted with an amine of formula IV II, it is advantageous to work at a temperature between 100 and 200 ⁰ C with an excess of amine and in the presence γόη traces of metallic sodium.

-5-

409817/1 195

The reaction between a halide of the acid of the formula II and an alcohol of the formula III or a Amine of Formula IV is carried out in a non-polar solvent, such as benzene or toluene, and then is heated to the boiling point, a tertiary base (such as triethylamine or Py- j ridin) or an excess of amine as such or an excess of j shot of alcohol, if it contains a basic group, I. is applied. ι

The compounds of formula I can also be prepared by reacting a metal salt of the acid of formula II in a solvent such as acetone or _t Methyläthy! Ketone, with a halogen compound of the formula

Br-HaI (V). ■:

are carried out, In which R has the above meaning and Hal is halogen, such as chlorine or bromine.

Another manufacturing process consists of Implementation of pyrocatechol in a compound of the formula

CQ-X '

HaI-CB "CVD

■: Hal - GH-Ar

In which Hal a halogen atom and Ar and X have the above meaning. Cyclislerungsreaktlon piping is preferably '· in a hydroxyl-containing solvent such as methanol, in the presence of a condensing agent such as Hatrimm oxide executed. It is also possible to work in another solvent, such as acetone, in the presence of, for example, potassium carbonate.

-6-

The benzodioxane derivatives of the formula I have in- ϊ

interesting pharmacological properties and have:

depending on the substituents present, antipyretic, an- ^! algesic, antipyretic, antitussive, local anesthetic and antiarrhythmic effects on and inhibit the central nervous system. You can use it externally, orally or

by injection as suitable pharmaceutical formulation \

in solid liquid or suspended form (e.g. ί

as juices, lotions, tablets, capsules ,. Ampoules or _:

Syrups). , ί

The following example serves to further explain the invention.

The melting and boiling points are given in degrees Celsius and not corrected. The identity of the substances and their purity were determined by elemental analysis of C, H, Έ (and halogen, if present), infrared spectra, IMB and UV spectra.

3-Pheny 1-1,4-benzodioxan-2-y! -Carboxylic acid and its Esters were prepared according to the method of V. Rosnati, F. Sannicolo and G. Pagani, Gazz.Chim. Italiana 98 (1968) page; Manufactured in 1069.

Preparation of 3-phenyl-1,4-benzodiQxan-2-yl-earbohydroxamic acid

To 2.5 g of Ia dissolved in 75 ml of absolute CH ^ QH was added a solution of 3.5 g of SHgöH'HCl in 50 ml of CH ₅ OH: and after filtering I 13.5 g of ethyl-3- phenyl 1,4-benzodioxan-2-yl carboxylate added ^: added. The mixture was stirred for 30 minutes and the Me-; Ethanol was removed and the residue was cooled i

4 09817 / i195

and acidified with dilute acetic acid. The precipitate was filtered off and recrystallized from ethyl acetate. The product thus obtained had a melting point of 203 - 204 ⁰ C.

Production of morpholinoethoxyethyl (3-phenyl-1,4-benzodioxan-2-yl carboxylate

To a ^{heated to 100 0} C mixture of 13.3 g of methyl (3-phenyl-1,4-benzodioxan ~ 2-yl) carboxylate, 12.5 g of 2- (ß-morpholinoethoxy) ethanol and 215 ml of anhydrous A solution of sodium ethylate (prepared from 0.165 g of metallic sodium in 10 ml of absolute ethanol) was added in small portions to heptane. The heating was then continued until no more azeotropic ethanol-ethanol-heptane mixture distilled off. The reaction mixture was then evaporated to dryness. The residue was dissolved in water and extracted with diethyl ether. The organic phase was washed with water and dried over Na ^ SO λ. The solvent was distilled off in vacuo and the remaining oil was converted into the hydrochloride. The product thus obtained showed after recrystallization from alcohol-ether has a melting point of 162 - 163 ⁰ C.

For example £ iel__3_

Production of N, N-diethylaminoethoxyethyl- (3-phenyl-1,4-benzodioxan-2-yl-carboxylate)

To a suspension of 12.8 g of 3-phenyl-1,4-benzodioxan-2-yl-carboxylic acid St ■ Ϊ00 ml of 'CHCI ^ were 5.1 g of triethyl

, -8th- "

4098 17/1195

amine added. The mixture was cooled and 5.4 g of ethyl chlorocarbonate was added dropwise. After 15

Stirring for minutes, 8.8 g of Ν, Ν-diethylaminoethoxyethanol were added. After two hours, the mixture was treated with water, the organic phase was separated off and dried over 1 ^ SCL. The solvent was removed in vacuo and the Eückstand was converted to the citrate (melting point 73-74 ⁰ C from isopropanol).

"Beis |) iel._4_

Production of N, N-diethylaminoethyl- (3-phenyl-1,4-benzodioxan-2-yl-carboxylate)

12 g of N, N-diethylaminoethyl chloride dissolved in 20 ml of acetone were added to a suspension of 22 g of sodium (3-phenyl-1,4-benzodioxan-2-yl) carboxylate in 100 ml of anhydrous acetone. The mixture was stirred for 2 hours. The sodium chloride formed was filtered off and the filtrate was evaporated to dryness. The citrate was produced from the remaining oil; the melting point was 99 to 100 ^° C. (from ethyl acetate).

Beis £ ieJL_5

Production of N-isopropyl (3-phenyl-1,4-benzodioxan-2-yl) -carbox-ramid

18.1 g of PCIc were added in portions to 22 g of 3-phenyl-1,4-benzodioxan-2-yl) carboxylic acid in 300 ml of anhydrous benzene added with cooling. After 2 hours the reaction mixture was added to a cold solution of isopropylamine in

409817/1195

_Q 7352615

* - j / ~ "

added to anhydrous benzene. After stirring for 2 hours, the product was poured onto ice. The organic base was separated off, washed with water and finally dried over sodium sulfate. The solvent was removed in vacuo. The residue was recrystallized from isopropyl alcohol and had a melting point of 196 to 198 ^° C.

N- (3-phenyl-1,4-benzodioxan-2-yl-carbonyl) -morpholine, ■ (melting point 148 to 150 ⁰ C from alcohol) was on analogous'

Way made. !

■. "ί

Example 6

Preparation of 1- (3J ¹ , N'-diethylaminoethyl) -3-phenyl-1,4-benzodioxan-2-yl -) - carboxamide

10 g of methyl (3-phenyl-1,4-benzodioxan-2-yl -) - carboxylate were added to 13 g of Ν, Ν-diethylethylenediamine, in which 10 mg of metallic sodium had been dissolved. The mixture was heated in a stream of nitrogen until all of the methanol formed in the reaction was distilled off. The excess amine was then removed in vacuo _; separates. The residue was recrystallized from benzene-hexane and had a melting point of 90 to 92 ⁰ C.

I-Benzyl- (3-phenyl-1,4-benzodioxan-2-yl) -carboxamides (melting point 171 to 172 ⁰ C from CH ₃ OH) and N-phenyl-N'-O-phenyl-1,4- benzodioxan-2-yl-carbonyl) -piperizinmonohydrat (melting point 241-242 ⁰ C from alcohol-water) 'were prepared in an analogous manner. ":

-10-

409 8 1 7/1195

Claims (15)

- ίο - Claims: Compounds of the general formula (I) or of their pharmaceutically acceptable salts, where Ar is a monocarbocyclic, substituted or unsubstituted aryl group and X is an OR-G group ₉ in which R is hydroxyalkyl, "^ -aminoalkyl or w-Amii ^ oalk- mean oxyalkyl or an -N group in which E ₂ R-, and Rp are identical or different and are hydrogen, Hydroxyl, medrigalkyl, carbocyclic monocyclic Aryl or low molecular weight monocarbocyclic arylalkyl or the substituents R-, and Rp together an I, I-alkylenimino, a Ν, Ν-oxoalkylenimino-, an N, I-thioalkylenimino- or a Ν, Ν-azoalkylenimino group, in which the alkylene has 3 to 8 carbon atoms and the aza nitrogen can be substituted. 2. Compounds according to claim 1, characterized in that Ar is phenyl, lower alkylphenyl, Trifluoromethylphenyl, lower alkoxyphenyl, or halophenyl. -11- 409817/1195 BATH 3. 3-phenyl-1,4-benzo-dioxan-2-yl-carbohydroxamic acid, 4. Morpholinoäthoxyäthyl- (3-phenyl-1,4-benzodioxan-2-yl) -car "boxylat _.: 5. N, N-diethylaminoethoxyethyl (3-phenyl-1,4-benzodioxan-2-yl) carboxylate. 6. N, N-diethylaminoethyl (3-phenyl-1,4-benzodioxan-2-yl) carboxylate. '. 7 I-isopropyl- (3-phenyl-1,4-benzodioxan-2-yl) -carb-; oxamide. i 8. N- (3-Phenyl-1,4-benzodioxan-2-yl-carbonyl) -morpholine. 9. N- (I ^f -, W ^f -diethylaiiiinoäthyl) - (3-phenyl-1,4-benzodiJ oxan-2-yl) carboxamide. 10. N-Benzyl- (3-phenyl-1,4-benzodioxan-2-yl -) - carb- j oxamide. ■ j 11.- li-Phenyl-li ^f - (3-phenyl-1,4-henzodioxan-2-yl-carbonyl) -piperazine. 12. A method for preparing the compounds according to] claim 1, characterized in that a compound the formula -12 -40 9817/119 5 " (II) in which Ar has the same meaning as in claim 1, or a suitable derivative thereof, with an alcohol E-OH or an amine of the formula in which R, IL and R _{2 have the} same meaning as in claim 1. 13- A method for producing the compound according to claim 1, characterized in that one a metal salt of an acid of the formula II reacts with a halogen compound of the formula R-Hal, in which R has the same meaning as in claim 1 and Hal has the meaning of halogen. 14. A method for preparing the compound according to claim 1, characterized in that pyrocatechol with a compound of the formula COX PaI-CH HaI-CH-Ar —13— 409817/1195 21352615 implements, in which Ar has the same meaning as in claim 1 and Hal has the meaning τοη halogen ". 15. A pharmaceutical composition containing as active substance one or more compounds according to claims 1 to 11 as a free base or pharmaceutical acceptable salt, and a pharmaceutically acceptable carrier. +49 9 817/1195